Prominent tauopathy and intracellular β-amyloid accumulation triggered by genetic deletion of cathepsin D: implications for Alzheimer disease pathogenesis
Abstract Background Cathepsin D (CatD) is a lysosomal protease that degrades both the amyloid-β protein (Aβ) and the microtubule-associated protein, tau, which accumulate pathognomonically in Alzheimer disease (AD), but few studies have examined the role of CatD in the development of Aβ pathology an...
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| Format: | Article |
| Language: | English |
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BMC
2024-04-01
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| Series: | Alzheimer’s Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13195-024-01443-6 |
| _version_ | 1797220026709704704 |
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| author | Heather M. Terron Sagar J. Parikh Samer O. Abdul-Hay Tomoko Sahara Dongcheul Kang Dennis W. Dickson Paul Saftig Frank M. LaFerla Shelley Lane Malcolm A. Leissring |
| author_facet | Heather M. Terron Sagar J. Parikh Samer O. Abdul-Hay Tomoko Sahara Dongcheul Kang Dennis W. Dickson Paul Saftig Frank M. LaFerla Shelley Lane Malcolm A. Leissring |
| author_sort | Heather M. Terron |
| collection | DOAJ |
| description | Abstract Background Cathepsin D (CatD) is a lysosomal protease that degrades both the amyloid-β protein (Aβ) and the microtubule-associated protein, tau, which accumulate pathognomonically in Alzheimer disease (AD), but few studies have examined the role of CatD in the development of Aβ pathology and tauopathy in vivo. Methods CatD knockout (KO) mice were crossed to human amyloid precursor protein (hAPP) transgenic mice, and amyloid burden was quantified by ELISA and immunohistochemistry (IHC). Tauopathy in CatD-KO mice, as initially suggested by Gallyas silver staining, was further characterized by extensive IHC and biochemical analyses. Controls included human tau transgenic mice (JNPL3) and another mouse model of a disease (Krabbe A) characterized by pronounced lysosomal dysfunction. Additional experiments examined the effects of CatD inhibition on tau catabolism in vitro and in cultured neuroblastoma cells with inducible expression of human tau. Results Deletion of CatD in hAPP transgenic mice triggers large increases in cerebral Aβ, manifesting as intense, exclusively intracellular aggregates; extracellular Aβ deposition, by contrast, is neither triggered by CatD deletion, nor affected in older, haploinsufficient mice. Unexpectedly, CatD-KO mice were found to develop prominent tauopathy by just ∼ 3 weeks of age, accumulating sarkosyl-insoluble, hyperphosphorylated tau exceeding the pathology present in aged JNPL3 mice. CatD-KO mice exhibit pronounced perinuclear Gallyas silver staining reminiscent of mature neurofibrillary tangles in human AD, together with widespread phospho-tau immunoreactivity. Striking increases in sarkosyl-insoluble phospho-tau (∼ 1250%) are present in CatD-KO mice but notably absent from Krabbe A mice collected at an identical antemortem interval. In vitro and in cultured cells, we show that tau catabolism is slowed by blockade of CatD proteolytic activity, including via competitive inhibition by Aβ42. Conclusions Our findings support a major role for CatD in the proteostasis of both Aβ and tau in vivo. To our knowledge, the CatD-KO mouse line is the only model to develop detectable Aβ accumulation and profound tauopathy in the absence of overexpression of hAPP or human tau with disease-associated mutations. Given that tauopathy emerges from disruption of CatD, which can itself be potently inhibited by Aβ42, our findings suggest that impaired CatD activity may represent a key mechanism linking amyloid accumulation and tauopathy in AD. |
| first_indexed | 2024-04-24T12:43:00Z |
| format | Article |
| id | doaj.art-c8e7a6b3cbd440008791292cdd23c305 |
| institution | Directory Open Access Journal |
| issn | 1758-9193 |
| language | English |
| last_indexed | 2024-04-24T12:43:00Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj.art-c8e7a6b3cbd440008791292cdd23c3052024-04-07T11:10:54ZengBMCAlzheimer’s Research & Therapy1758-91932024-04-0116111210.1186/s13195-024-01443-6Prominent tauopathy and intracellular β-amyloid accumulation triggered by genetic deletion of cathepsin D: implications for Alzheimer disease pathogenesisHeather M. Terron0Sagar J. Parikh1Samer O. Abdul-Hay2Tomoko Sahara3Dongcheul Kang4Dennis W. Dickson5Paul Saftig6Frank M. LaFerla7Shelley Lane8Malcolm A. Leissring9Institute for Memory Impairments and Neurological Disorders, University of California, Irvine (UCI MIND)Institute for Memory Impairments and Neurological Disorders, University of California, Irvine (UCI MIND)Department of Neuroscience, Mayo Clinic FloridaDepartment of Neuroscience, Mayo Clinic FloridaDepartment of Neuroscience, Mayo Clinic FloridaDepartment of Neuroscience, Mayo Clinic FloridaInstitut für Biochemie, Christian-Albrechts-Universität zu KielInstitute for Memory Impairments and Neurological Disorders, University of California, Irvine (UCI MIND)Institute for Memory Impairments and Neurological Disorders, University of California, Irvine (UCI MIND)Institute for Memory Impairments and Neurological Disorders, University of California, Irvine (UCI MIND)Abstract Background Cathepsin D (CatD) is a lysosomal protease that degrades both the amyloid-β protein (Aβ) and the microtubule-associated protein, tau, which accumulate pathognomonically in Alzheimer disease (AD), but few studies have examined the role of CatD in the development of Aβ pathology and tauopathy in vivo. Methods CatD knockout (KO) mice were crossed to human amyloid precursor protein (hAPP) transgenic mice, and amyloid burden was quantified by ELISA and immunohistochemistry (IHC). Tauopathy in CatD-KO mice, as initially suggested by Gallyas silver staining, was further characterized by extensive IHC and biochemical analyses. Controls included human tau transgenic mice (JNPL3) and another mouse model of a disease (Krabbe A) characterized by pronounced lysosomal dysfunction. Additional experiments examined the effects of CatD inhibition on tau catabolism in vitro and in cultured neuroblastoma cells with inducible expression of human tau. Results Deletion of CatD in hAPP transgenic mice triggers large increases in cerebral Aβ, manifesting as intense, exclusively intracellular aggregates; extracellular Aβ deposition, by contrast, is neither triggered by CatD deletion, nor affected in older, haploinsufficient mice. Unexpectedly, CatD-KO mice were found to develop prominent tauopathy by just ∼ 3 weeks of age, accumulating sarkosyl-insoluble, hyperphosphorylated tau exceeding the pathology present in aged JNPL3 mice. CatD-KO mice exhibit pronounced perinuclear Gallyas silver staining reminiscent of mature neurofibrillary tangles in human AD, together with widespread phospho-tau immunoreactivity. Striking increases in sarkosyl-insoluble phospho-tau (∼ 1250%) are present in CatD-KO mice but notably absent from Krabbe A mice collected at an identical antemortem interval. In vitro and in cultured cells, we show that tau catabolism is slowed by blockade of CatD proteolytic activity, including via competitive inhibition by Aβ42. Conclusions Our findings support a major role for CatD in the proteostasis of both Aβ and tau in vivo. To our knowledge, the CatD-KO mouse line is the only model to develop detectable Aβ accumulation and profound tauopathy in the absence of overexpression of hAPP or human tau with disease-associated mutations. Given that tauopathy emerges from disruption of CatD, which can itself be potently inhibited by Aβ42, our findings suggest that impaired CatD activity may represent a key mechanism linking amyloid accumulation and tauopathy in AD.https://doi.org/10.1186/s13195-024-01443-6TauopathyNeurofibrillary tanglesAmyloid-β proteinCathepsin DAlzheimer diseaseLysosomes |
| spellingShingle | Heather M. Terron Sagar J. Parikh Samer O. Abdul-Hay Tomoko Sahara Dongcheul Kang Dennis W. Dickson Paul Saftig Frank M. LaFerla Shelley Lane Malcolm A. Leissring Prominent tauopathy and intracellular β-amyloid accumulation triggered by genetic deletion of cathepsin D: implications for Alzheimer disease pathogenesis Alzheimer’s Research & Therapy Tauopathy Neurofibrillary tangles Amyloid-β protein Cathepsin D Alzheimer disease Lysosomes |
| title | Prominent tauopathy and intracellular β-amyloid accumulation triggered by genetic deletion of cathepsin D: implications for Alzheimer disease pathogenesis |
| title_full | Prominent tauopathy and intracellular β-amyloid accumulation triggered by genetic deletion of cathepsin D: implications for Alzheimer disease pathogenesis |
| title_fullStr | Prominent tauopathy and intracellular β-amyloid accumulation triggered by genetic deletion of cathepsin D: implications for Alzheimer disease pathogenesis |
| title_full_unstemmed | Prominent tauopathy and intracellular β-amyloid accumulation triggered by genetic deletion of cathepsin D: implications for Alzheimer disease pathogenesis |
| title_short | Prominent tauopathy and intracellular β-amyloid accumulation triggered by genetic deletion of cathepsin D: implications for Alzheimer disease pathogenesis |
| title_sort | prominent tauopathy and intracellular β amyloid accumulation triggered by genetic deletion of cathepsin d implications for alzheimer disease pathogenesis |
| topic | Tauopathy Neurofibrillary tangles Amyloid-β protein Cathepsin D Alzheimer disease Lysosomes |
| url | https://doi.org/10.1186/s13195-024-01443-6 |
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